In the human, the [unreadable]-opioid receptor gene contains numerous single nucleotide polymorphisms (SNPs), including at least seven in the coding region that alter amino acids in the receptor. Among these, an emerging relevance for N40D (or A118G in the DNA) stems from its association with clinical responses to opioidergics, alcohol and opiate sensitivity and dependence, methamphetamine psychosis, aberrant hypothalamic-pituitary- adrenal (HPA) axis function and epilepsy. We discovered a novel P26R SNP in the rhesus monkey [unreadable]-opioid receptor that both functionally and phenotypically parallels human N40D. Both human and rhesus monkey alleles have 3.5-fold greater sensitivity to p-endorphin, and associate with altered hypothalamic-pituitary- adrenal (HPA) axis function. Based on these data, we will develop the rhesus monkey as a naturalistic model of human genotype/phenotype relationships relevant to [unreadable]-opioid receptor diversity in humans. We will identify SNPs occurring within the coding region and compare their functional consequences to human SNPs in vitro. Because one of the most prominent and biomedically significant commonalities among humans and rhesus monkeys is the parallel pathogenesis and disease progression of Acquired Immune Deficiency Syndrome (AIDS), we include a focus on [unreadable]-opioid receptor expression in immune cells and its documented interaction with CCR5, the major co-receptor for Human and Simian Immunodeficiency Virus (HIV/SIV) entry into cells. As [unreadable]-opioid receptor agonists affect CCR5 signaling, modulate CCR5 gene expression and regulate SIV/HIV infectivity, we will explore an unknown area: do SNPs in the [unreadable]-opioid receptor contribute as a host factor in AIDS? Accordingly, the Aims of this grant are to: 1) identify allelic variants of the rhesus monkey |a-opioid receptor that affect protein structure, and develop genotyping assays to screen for the common alleles; 2) clone full-length variant coding regions of the rhesus monkey [unreadable]-opioid receptor, express each clone and assess its pharmacology along side human variants; and 3) explore whether [unreadable]-opioid receptor genotype influences how endogenous opioid peptides, common opiates and clinically relevant opioidergic drugs regulate CCR5 and thereby contribute as a relevant host factor in AIDS infection and progression. The structural similarity of human and rhesus monkey [unreadable]-opioid receptors and the functional and phenotypic characteristics that are common to both species may permit the development of rhesus monkeys as an unparalleled naturalistic model that most accurately represents human [unreadable]-opioid receptor physiogenetics and pharmacogenetics. [unreadable] [unreadable]